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Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate

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  • Zhenhua Wang

    (University of Science and Technology of China)

  • Jingjing He

    (University of Science and Technology of China)

  • Yufan Yang

    (University of Science and Technology of China)

  • Yonglin He

    (University of Science and Technology of China)

  • Hongwu Qian

    (University of Science and Technology of China)

Abstract

The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.

Suggested Citation

  • Zhenhua Wang & Jingjing He & Yufan Yang & Yonglin He & Hongwu Qian, 2025. "Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate," Nature Communications, Nature, vol. 16(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58087-9
    DOI: 10.1038/s41467-025-58087-9
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